Ligand Based Drug Discovery Of Novel Dengue-2 Ns2b-Ns3 Protease Inhibitors
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Date
2015-08
Authors
Mohd Nawi, Mohamed Sufian
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Abstract
The reported dengue cases are increasing yearly, yet no anti-dengue agent is available in the market. Therefore, the search for anti-dengue is critical. In Malaysia, Dengue-2 (DEN-2) is the most prevalent serotype. NS2B-NS3 protease is the enzyme for the cleavage of polyprotein precursor, which is crucial for the flavivirus replications. This makes it a potential target for the development of therapeutics against the dengue virus. In this study, ligand-based approach was implemented in searching for the new potential DEN-2 NS2B-NS3 protease inhibitors. Pharmacophore models were developed from diverse reported structures of DEN-2 NS2B-NS3 protease inhibitors, comprising peptide and non-peptide molecules. The selected pharmacophore models were employed to screen the US National Cancer Institute (NCI) list of compounds to search for new DEN-2 NS2B-NS3 protease inhibitors. The list of natural products in Natural Product Discovery System (NADI) database was also screened and the structures of active hits were exploited for the design of new inhibitor molecules. The designed molecules were then synthesised. The in-vitro assay were conducted to examine the inhibitory activities of the selected hits from NCI database and the synthesised compounds towards recombinant DEN-2 NS2B-NS3 protease by using fluorogenic peptide substrate Boc-Gly-Arg-Arg-MCA. The validity of selected pharmacophore models, S5T5H06 and S2T3H01 was experimentally established by the identification of three new DEN-2 protease inhibitors retrieved from NCI database with Ki values of 17 ± 6 μM (non-competitive), 26 ± 4 μM (competitive) and 95 ± 35 μM (competitive). One competitive inhibitor (Ki = 78 ± 41 μM) and two non-competitive inhibitors (Ki = 29 ± 6 μM and Ki = 97 ± 49 μM) were found from the NADI guided compounds. This interesting finding revealed that the natural products from Malaysian biodiversity, which are available in NADI database, are valuable resources of active compounds/active fragments for the development of anti-dengue. It was postulated that the active site and the allosteric binding site on DEN-2 protease share common binding mode to the ligand that carry the pharmacophores of the model S5T5H06. From SAR study, a potential lead structure for DEN-2 NS2B-NS3 protease non-competitive inhibitor was suggested. The structure should has a central nucleus made up of diphenylmethane connected by imines at the position 1,1’ to two phenyl lateral arms, R1 and R2. Additionally, the structure should have a hydrophobic and a hydrogen bond acceptor (HBA) as side chains to the phenyl group R1 and a hydrogen bond donor (HBD) as a side chain to the phenyl group R2. The findings concluded that pharmacophoric models S5T5H06 and S2T3H01 can be useful for pharmacophoric exploration of chemical databases in searching for the potential DEN-2 NS2B-NS3 protease inhibitors as well as a guide to design new potential inhibitors from the active hits.
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Pharmacy